This invention relates to a novel process for preparing 9-(2,6-dihalobenzyl)adenines. Said adenines are described in U.S. Pat. No. 3,846,426 as being useful in the treatment and prevention of coccidoisis.
Coccidiosis is a widespread poultry disease which is produced by infections of protozoa of the genus Eimeria which causes severe disorders in the intestines and ceca of poultry. Some of the most significant of these species are E. tenella, E. acervulina, E. necatrix, E. brunetti and E. maxima. This disease is generally spread by the birds picking up the infectious organism in droppings on contaminated litter or ground, or by way of food drinking water. The disease is manifested by hemorrhage, accumulation of blood in the ceca, passage of blood in the droppings, weakness and digestive disturbances. The disease often terminates in the death of the animal, but the fowl which survive severe infections have had their market value substantially reduced as a result of the infection. Coccidiosis is, therefore, a disease of great economic importance and extensive work has been done to find new and improved methods for controlling and treating coccidial infections in poultry.
Prior art base catalyzed alkylations of adenine were carried out in aqueous solvents or aqueous protic organic solvents. These reactions were homogenous and rapid but suffered from the disadvantage that mixtures of 3-isomer and 9-isomer were obtained which contain a high proportion of 3-isomer. The 3-isomer and 9-isomer can be exemplified by the following structural formulas: ##STR1## Base catalyzed alkylations of adenine carried out in aprotic solvents such as dimethylformamide and dimethylsulfoxide provide a higher ratio of 9-isomer with respect to 3-isomer but suffer from the disadvantage that these solvents are costly. The isolation of the product is also made more difficult. The reaction mixture has to be quenched in water and the product, collected by filtration, has to be repeatedly washed to remove solvent. This results in a reduction of yield.
Solvents such as dimethylformamide and dimethylsulfoxide do not dissolve the alkali metal or alkaline earth metal salts of adenine to any great extent, however, the fraction which does dissolve is highly dissociated and results in a "naked adenine anion" or a "loose ion pair" which is rapidly alkylated. According to the process of the present invention, the salt of adenine is transported from a solid phase or an aqueous phase by the action of a "phase transfer catalyst" into an aprotic organic solvent phase in which phase alkylation takes place. The advantage of the present invention is that alkylations can be carried out in aprotic solvents in which the alkali metal or alkaline metal salts are otherwise insoluble or in which, if solution occurs, very little dissociation occurs and alkylation is slow due to lack of "naked adenine anions".
The present invention differs from the process of the prior art in that a "phase transfer catalyst", either an ammonium or phosphonium salt, is present which enhances the rate of alkylation and enables the reaction to be carried out in an aprotic solvent in which alkali and alkaline earth metal salts of adenine are not generally soluble. Carrying out the alkylation in aprotic solvents yields predominately the 9-isomer. "Phase transfer catalysts" also allow one to carry out the alkylation at room temperature and for short reaction periods to obtain a product containing a high ratio of 9-isomer with respect to 3-isomer. For example, alkylations carried out in acetone are accelerated as much as five to ten-fold without affecting selectivity when carried out in the presence of a "phase transfer catalyst".
The role of the "phase transfer catalysts" is presumed to be to convert the alkali or alkaline earth metal salts of adenine to tetraalkyl ammonium or tetraalkyl of phosphonium salts. The resulting ammonium and phosphonium salts of adenine are more soluble and readily dissociated in the organic phase in which phase alkylation occurs. Accordingly, the ammonium or phosphonium salts catalyze the transport of adenine from either an aqueous phase or a solid phase into an organic phase. Hence, these salts are herein referred to as "phase transfer catalysts".